Protocol deviations should be collected throughout the
study (beyond only the inclusion /exclusion criteria). If it is a randomized
study, we can classify the protocol deviations as pre-randomization and post
randomization. If it is non-randomized study, we can classify the protocol
deviations as pre-dose and post-dose.

Prior to the randomization or dosing, the eligibility
criteria (inclusion and exclusion criteria) should be verified. If subjects do
not meet any of the inclusion and exclusion criteria, but are enrolled into the
study, the violation of inclusion/exclusion criteria must be recorded. Some
people may use the term 'protocol violation' specifically for those deviations
that are related to the inclusion and exclusion criteria.

According to the SDTM
implementation guide, the pre-randomization protocol deviations (i.e.,
violation of inclusion/exclusion criteria) should be collected in IE domain and
the post-randomization protocol deviations need to be collected in DV domain.

Can we allow the protocol deviation waiver?

A protocol waiver is an intentional deviation
from the approved protocol, such as the enrollment of a participant in
violation of the protocol’s inclusion/exclusion criteria. Most sites realize
that it is necessary to obtain the sponsor’s approval prior to implementing a
protocol waiver. It is also necessary, however, to obtain the IRB’s approval
prior to implementing a protocol waiver, unless the change is deemed necessary to
eliminate an apparent immediate hazard for study participants' safety. In
practice, many clinical trial sponsors will allow the protocol deviation waiver
and allow the subjects without meeting one or more inclusion / exclusion
criteria to be enrolled into the study. Here are some discussions about the
waiver for protocol deviations:

Adherence to the protocol is a fundamental part of the conduct of
a clinical study. Any significant change to the protocol should be submitted as
an amendment to the competent regulatory authority and ethics committee.
Significant changes to the protocol include any change in inclusion and
exclusion criteria, addition or deletion of tests, dosing, duration of
treatment etc (see the definition of a substantial amendment in the 'detailed
guidance for the request for authorisation of a clinical trial on a medicinal
product for human use to the competent authorities, notification of substantial
amendments and declaration of the end of the trial' published by the European
Commission in chapter I, volume 10 of the rules governing medicinal products in
the European Community). Deviations from the inclusion/exclusion criteria
of the protocol might erode the scientific and ethical value of the protocol
and its authorisation and might have an impact on the processes put in place
for the care and safety of the study subjects.

Sponsors and investigators should not use systems of
prospectively approving protocol deviations, in order to effectively widen the
scope of a protocol. Protocol design should be appropriate to the
populations required and if the protocol design is defective, the protocol
should be amended.

GCP does permit deviations from the protocol when necessary to
eliminate immediate hazards to the subjects but this should not normally arise
in the context of inclusion/exclusion criteria, since the subject is not yet
fully included in the trial at that point in the process GCP inspectors have
observed a number of sponsors implementing systems where the investigator can
contact the sponsor, usually the Medical Monitor, and request a prospective
approval to deviate from the inclusion and/or exclusion criteria. The use
of such systematic waiver systems in clinical trials is not considered to be
appropriate and studies using such a system might be regarded as non-compliant
with GCP.

Can we allow rescreening for subjects who failed one of the
inclusion / exclusion criteria?

For some inclusion/exclusion criteria that are based on the laboratory
measurements, lung functional test, six-minutes walking test,… subjects may be
screening failures due to not meeting one of the criteria. For example, if one
of the inclusion criteria requires hemoglobin level must be greater than 9 g/dl, a subject may just miss the
criteria (for example, hemoglobin level is 8.9 g/dl) that could be caused by the measurement error. If the protocol specifies
that the rescreening is allowed, the subject may come back for a rescreening
and have another lab test for hemoglobin level. I have seen many clinical trial
protocols that allow the rescreening, especially in the chronic disease clinical
trials.

It is obvious that the rescreening
will not be feasible for clinical trials in acute diseases for example, in clinical
trials in ischemic stroke patients.

Where to document and maintain the protocol deviations?

The protocol deviations are usually documented by the clinical team
(study manager and clinical monitors) and oversight group. In early days, the
protocol deviation may just be entered and maintained in an excel spreadsheet. Nowadays,
the protocol deviations are usually documented and maintained in CTMS (clinical
trial management system).

Can protocol deviations be collected through EDC?

The protocol deviations can also be directly documented and
maintained within EDC system where a separate case report form (CRF) is designed specifically for
collecting the protocol deviations. Clinical monitors (CRAs) are given the
access to enter and maintain the protocol deviation through EDC system. The investigator/study coordinators at sites will not have access to the protocol deviation CRF.

Site level versus subject level protocol deviations

While majority of the protocol deviations are on the subject
level, the protocol deviations can be on the site-level that have impacts on
all subjects enrolled at that specific site.

The site level and subject level protocol deviation need to be distinguished
in the protocol deviation tracking.

CDISC SDTM implementation guide indicates that the protocol deviations will be captured in DV domain (see the explanations of the DV domain below). Notice that current SDTM standard is designed for subject data with the only exception of Trial Design info. Therefore, the DV domain is only for the subject-level protocol deviations. If there are site level protocol deviation (violations), the suggestion is not to be included in the DV dataset, but included in protocol deviation tracking and described in the clinical study report. It is also a good practice to indicate in Study Data Reviewer’s Guide how the site-level protocol deviations are handled.

How will the protocol deviation information be used?

The protocol deviation information will be converted into the data set as part of the clinical database.

The protocol deviations in DV domain will be provided in data
listing and will be summarized (by treatment group and by protocol deviation
category). The violation of the inclusion/exclusion criteria may be separately
listed and summarized.

In clinical study report, according to ICH
E3, section 10.2 is for describing the inclusion / exclusion criteria
violation and protocol deviations